Deafness and balance dysfunction are common human disabilities. In the majority of cases these disabilities result from the loss of sensory hair cells in the (1) organ of Corti (OC) in the cochlea, (2) the vestibular epithelium in the cristae or (3) saccule or utricle of the vestibular organ. Currently there is no FDA approved treatment that can cure these disorders by restoring the sensory hair cells in these tissues.
Current approaches to the problem involve vestibular rehabilitation to allow adaptation to the injury to the vestibular organs. The rehabilitation is time consuming, and does not restore lost function. For sensorineural deafness, rehabilitation can be achieved with hearing aids or cochlear implants. However, these devices are expensive, require an extensive surgery and produce a subnormal sound quality and only partial return of function.
Another approach in treating hearing disorders is administration of peptides or other small molecules. Often treatment results are limited with the use of such due to relatively high cochlear concentrations that must be achieved (micro or millimolar). Moreover, protein or peptide inhibitors are difficult to deliver systemically to treat the ear due to the blood labyrinthine barrier and protein clearance in the bloodstream as well as potential antigenicity. Difficulties also exist in terms of delivering adequate concentrations of peptide and protein directly to the cochlea as well, particularly using topical delivery due to the size of the molecule.
One potential alternative to these traditional approaches is using targeted gene therapy to induce inner ear hair cell regeneration and replacement. For example, hair cell regeneration or replacement has been achieved in rodents through the use of a viral vector to introduce the Atoh1 gene into inner ear sensory epithelium. However, this approach carries risk inherent in viral vector therapy including the induction of infection, an inflammatory immune response, genetic mutation, development of neoplasia and others. Silencing of kip1p27 RNA has been shown to induce hair cell regeneration but in an ectopic fashion without return of function. Modulation of the retinoblastoma gene can also produce additional hair cells but there may be danger inherent in manipulating an oncogene, or cancer causing gene. Thus, current gene therapies directed to regeneration or replacement of inner ear hair cells have failed to identify a safe and effective molecular target and delivery method.
One potential gene therapy approach is through the use of short interfering RNA (siRNA). Once introduced into a cell, the siRNA molecules complex with the complimentary sequences on the messenger RNA (mRNA) expressed by a target gene. The formation of this siRNA/mRNA complex results in degradation of the mRNA through a natural intracellular processes known as RNA interference (RNAi). RNAi is a well-established tool for identifying a gene's function in a particular cellular process and for identifying potential therapeutic targets in disease models. Although RNAi has traditionally been used in cell culture and in vitro applications, gene-therapy based therapeutics are now being explored utilizing this process.
As discussed above, several gene targets have been explored with respect to regeneration of hair cells of the inner ear without much success. The basic helix-loop-helix (bHLH) genes Hes1 and Hes5 have been identified as playing roles in sensory hair cell development in the cochlea and vestibular structures of the ear. In addition, a potential gene target for preventing loss of hair cells is mitogen-activated protein kinase 1 (MAPK1), which plays a role in programmed cell death or apoptosis. However, the potential for these to be effective therapeutic targets for regeneration or protection of sensory hair cells of the inner ear has yet to be demonstrated and or identified as a viable approach.